The characterization of normal and abnormal proteins involved in genetic disorders affecting the nervous system permits the isolation of cDNA and genomic DNA that can be used to develop treatments for inherited disorders using gene therapy. Particularly suited for initial attempts at gene therapy have been those disorders in which the systemic and neurologic manifestations of the disorder are the consequence of abnormalities of the more readily accessible bone marrow derived cells. In these instances the transfer of normal genes to bone marrow progenitor cells is a rationale therapeutic approach. Using the lysosomal disorder Gaucher disease as a model to develop more efficient techniques for gene transfer, we have successfully used retroviral vectors to transfer and express human glucocerebrosidase in mouse and Gaucher patient cell lines and tissues. Receptor and liposome mediated, as well as direct naked DNA transfer into specific tissues are among other strategies being investigated. In utero gene transfer in mice is also being studied, and may be required for effective treatment of disorders affecting the nervous system. An initial goal of this research is the application of gene therapy to the non-neuronopathic phenotypes of genetic disorders that can, in some cases, also affect the nervous system. Transgenic animal models have been developed using targeted homologous recombination in embryonic stem cells to generate mouse models of human disease and these animal models are used to test novel treatment strategies. We have successfully used retrovirus vectors encoding human glucocerebrosidase to correct the enzyme deficiency and reverse storage of lipid in tissues in murine models of Gaucher diseases. We have also used retroviral mediated transfer of neurotransmitter synthesizing enzymes such as tyrosine hydroxylase for both the in vitro and in vivo correction of DOPA deficiency states. Recombinantly engineered cells (for instance, fibroblasts) producing tyrosine hydroxylase have been used as depots of L-DOPA release and have been transplanted into the nervous system of animal models. When our understanding of the pathogenetic mechanisms of inherited neurologic and psychiatric disease improves and as technologies for the transfer and expression of genes in specific tissues ad cells becomes more predictable, we may be able to extend the use of gene therapy to treatment of other selected disorders affecting the nervous system.